Intrathecal injection of the sigma(1) receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain.
BACKGROUND
Selective blockade of spinal sigma(1) receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain.


METHODS
Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats.


RESULTS
BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation.


CONCLUSIONS
These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.
Roh
Dae-Hyun
DH
College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, Republic of Korea.
Kim
Hyun-Woo
HW
Yoon
Seo-Yeon
SY
Seo
Hyoung-Sig
HS
Kwon
Young-Bae
YB
Kim
Kee-Won
KW
Han
Ho-Jae
HJ
Beitz
Alvin J
AJ
Na
Heung-Sik
HS
Lee
Jang-Hern
JH
D000818:Animals; D005029:Ethylenediamines / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000517:prevention & control*; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D005029:Ethylenediamines; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin